Our long-term objectives are to understand the mechanism of Muller cell-photoreceptors interaction and to develop new strategies of neuroprotection for treating retinal degenerations. Retinal degenerations are a major cause of blindness for which no effective treatments are available. It is estimated that one in 3,500 to 4,000 people is affected by retinitis pigmentosa, a heterogeneous group of inherited retinal degenerative disorders. The major manifestation of retinitis pigmentosa is progressive degeneration of photoreceptors. We have two significant findings recently. One is the discovery that CNTF modulates the activities of photoreceptors. Another is that CNTF promotes regeneration of cone inner/outer segments and reverses cone's degenerating process. The effects of CNTF are likely mediated by Muller cells. The similarity between CNTF effects and light-induced photoreceptor plasticity lead us to believe that the latter is also mediated by Muller cells. We therefore hypothesize that Muller cells play a central role in controlling the behavior of photoreceptors. This proposal contains five Specific Aims. The first two focus on characterization of CNTF- and light-induced changes in rods. The third Specific Aim is to characterize secondary cone degeneration and the capability of CNTF to reverse the degenerative process. Specific Aim four will provide direct evidence to prove the central role of Muller cells in modulating the behavior of photoreceptors. In Specific Aim five, we want to identify a putative factor that Muller cells release to communicate with photoreceptors. Results from this proposal would have important implications both in retinal cell biology and in potential clinical application of CNTF for retinal neurodegeneration. Data from our proposed experiments would enhance our understanding of the role of Muller cells in the retina. The glia-neuron interaction in maintaining neurons at an optimal level of responsiveness in a changing environment may be pertinent to other parts of the nervous system. On the practical side, a better understanding of the mechanism of action will be essential for the development of CNTF for clinical use. Our demonstration that CNTF promotes regeneration of cone inner/outer segments would be of great clinical interest, since cones are the photoreceptors responsible for central and color vision. The identification of the putative soluble factor released from Muller cells would be the first step to develop it for clinical use.